Cytotoxic T-lymphocyte infiltration and chemokine predict long-term patient survival independently of tumor mutational burden in triple-negative breast cancer

Katsuta, Eriko; Yan, Li; Opyrchal, Mateusz; Kaliński, Paweł; Takabe, Kazuaki

doi:10.1177/17588359211006680

Cited by 13 publications

(10 citation statements)

References 45 publications

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“…Moreover, the significantly higher expression of CD8A and PD-1 in the inflammatory DAMPs subtype may be related to its better DFS and DMFS. These observations are in line with previous reports that TNBC patients with elevated CD8A ( 46 ) and PD-1 ( 47 ) expression can potentially benefit from ICIs. Additionally, these results were successfully validated with the TCGA public database.…”

Section: Discussionsupporting

confidence: 92%

Immunogenic Cell Death-Relevant Damage-Associated Molecular Patterns and Sensing Receptors in Triple-Negative Breast Cancer Molecular Subtypes and Implications for Immunotherapy

Zhong

et al. 2022

Front. Oncol.

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ObjectivesTriple-negative breast cancer (TNBC) is defined as a highly aggressive type of breast cancer which lacks specific biomarkers and drug targets. Damage-associated molecular pattern (DAMP)-induced immunogenic cell death (ICD) may influence the outcome of immunotherapy for TNBC patients. This study aims to develop a DAMPs gene signature to classify TNBC patients and to further predict their prognosis and immunotherapy outcome.MethodsWe identified the DAMPs-associated subtypes of 330 TNBCs using K-means analysis. Differences in immune status, genomic alterations, and predicted immunotherapy outcome were compared among each subtype.ResultsA total of 330 TNBCs were divided into three subtypes according to DAMPs gene expression: the nuclear DAMPs subtype, featuring the upregulation of nuclear DAMPs; the inflammatory DAMPs subtype, characterized by the gene set enrichment of the adaptive immune system and cytokine signaling in the immune system; and the DAMPs-suppressed subtype, having the lowest level of ICD-associated DAMPs. Among them, the inflammatory subtype patients had the most favorable survival, while the DAMPs-suppressed subtype was associated with the worst prognosis. The DAMPs subtyping system was successfully validated in the TCGA cohort. Furthermore, we systemically revealed the genomic alterations among the three DAMPs subtypes. The inflammatory DAMPs subtype was predicted to have the highest response rate to immunotherapy, suggesting that the constructed DAMPs clustering had potential for immunotherapy efficacy prediction.ConclusionWe established a novel ICD-associated DAMPs subtyping system in TNBC, and DAMPs expression might be a valuable biomarker for immunotherapy strategies. Our work could be helpful to the development of new immunomodulators and may contribute to the development of precision immunotherapy for TNBC.

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Section: Discussionsupporting

confidence: 92%

Immunogenic Cell Death-Relevant Damage-Associated Molecular Patterns and Sensing Receptors in Triple-Negative Breast Cancer Molecular Subtypes and Implications for Immunotherapy

Zhong

et al. 2022

Front. Oncol.

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“…CD8A and EIF2AK3 are essential ICD genes in prognostic models. It has been reported that in triple-negative breast cancer (TNBC) patients, the inflammatory DAMP subtype has the most significant proportion of CD8 T cells and is associated with the best predictive outcome, that M2-like macrophages in the suppressor subtype of DAMPs significantly increase inflammation, and that triple-negative breast cancers with high CD8A expression benefit from ICI ( 33 , 34 ). Xu et al.…”

Section: Discussionmentioning

confidence: 99%

Development and validation of prognostic index based on immunogenic cell death-related genes with melanoma

et al. 2022

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Although immune checkpoint inhibitors have improved the overall survival rate of skin cutaneous melanoma (SKCM) patients, there is a wide variation and low response rate to these treatments in clinical immunotherapy for melanoma patients. These problems can be addressed through the induction of immunogenic cell death (ICD).We constructed an ICD-based prognostic model to predict the prognosis of SKCM patients and the efficacy of immunotherapy. Information on melanoma and normal samples obtained by TCGA and GTEx was stratified by ICD-related genes. The samples were divided into two subtypes according to high and low expression of ICD using an unsupervised clustering method (K-means). Patients with ICD-high subtype showed longer overall survival. We found that the ICD-related differential genes were associated with several cell death and immune-related pathways through GO, KEGG and GSEA. Immunoscore and tumor purity of ICD-associated genes was calculated using ESTIMATE, and ICD-high subtypes had higher immunoscore and lower tumor purity than ICD-low subtypes. Seven ICD-associated genes were obtained by one-way Cox regression and Lasso regression of ICD genes. Risk models were constructed to classify melanoma patients into high- risk and low-risk groups. The expression of ICD-related pivotal genes was lower in the high-risk group than in the low-risk group, and the survival time was significantly higher in the low-risk group than in the high-risk group. We then found that ICD risk characteristics had predictive value for the clinical efficacy of immunotherapy, with higher ICD risk scores in the immunotherapy non-responsive group. Combined with clinicopathological factors, a nomogram was established. the ROC and calibration curves assessed the ability of the nomogram to predict prognosis. We developed a new classification system for SKCM based on the characteristics of ICDs. This stratification has important clinical implications for estimating the prognosis and immunotherapy of SKCM patients.

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“…Hazard ratios for overall survival were calculated using individual log-transformed gene expression. A ‘functional hotness score’ for combined expression of CD8A, DNAM-1, and NKG2D was calculated as previously described [ 51 ].…”

Section: Methodsmentioning

confidence: 99%

NK Receptors Replace CD28 As the Dominant Source of Signal 2 for Cognate Recognition of Cancer Cells by TAA-specific Effector CD8+ T Cells

Kalinski,

Dong,

Obermajer

et al. 2023

Preprint

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CD28-driven “signal 2” is critical for naïve CD8+ T cell responses to dendritic cell (DC)-presented weak antigens, including non-mutated tumor-associated antigens (TAAs). However, it is unclear how DC-primed cytotoxic T lymphocytes (CTLs) respond to the same TAAs presented by cancer cells which lack CD28 ligands. Here, we show that NK receptors (NKRs) DNAM-1 and NKG2D replace CD28 during CTL re-activation by cancer cells presenting low levels of MHC I/TAA complexes, leading to enhanced proximal TCR signaling, immune synapse formation, CTL polyfunctionality, release of cytolytic granules and antigen-specific cancer cell killing. Double-transduction of T cells with recombinant TCR and NKR constructs or upregulation of NKR-ligand expression on cancer cells by chemotherapy enabled effective recognition and killing of poorly immunogenic tumor cells by CTLs. Operational synergy between TCR and NKRs in CTL recognition explains the ability of cancer-expressed self-antigens to serve as tumor rejection antigens, helping to develop more effective therapies.

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Cytotoxic T-lymphocyte infiltration and chemokine predict long-term patient survival independently of tumor mutational burden in triple-negative breast cancer

Cited by 13 publications

References 45 publications

Immunogenic Cell Death-Relevant Damage-Associated Molecular Patterns and Sensing Receptors in Triple-Negative Breast Cancer Molecular Subtypes and Implications for Immunotherapy

Immunogenic Cell Death-Relevant Damage-Associated Molecular Patterns and Sensing Receptors in Triple-Negative Breast Cancer Molecular Subtypes and Implications for Immunotherapy

Development and validation of prognostic index based on immunogenic cell death-related genes with melanoma

NK Receptors Replace CD28 As the Dominant Source of Signal 2 for Cognate Recognition of Cancer Cells by TAA-specific Effector CD8+ T Cells

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